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THE JULES FRANÇOIS MEMORIAL LECTURE *
THE COLLABORATIVE OCULAR MELANOMA
STUDY AND MANAGEMENT OF CHOROIDAL
MELANOMA
BRADLEY R. STRAATSMA, M.D.**
Baron Jules François was the preeminent ophthalmologist in a generation that included a
number of notable colleagues. Throughout his
distinguished tenure as Professor and Director
of Ophthalmology at the University of Ghent,
he combined intellectual and scholarly achievement with extraordinary energy and global vision.
Scientific interests ranging from genetics1 to
glaucoma2 culminated in authorship of hundreds of articles, chapters, and books. His
boundless energy permitted an intense work
ethic at the University of Ghent, leadership as
President of the Royal Academy of Medicine of
Belgium (1969) and a broad commitment to
international ophthalmology.
Central to all activities, Jules François had a vision of ophthalmology as a global community.
While President of the International Council of
Ophthalmology from 1974 to 1982, he presided over the XXIII International Congress of
Ophthalmology in Tokyo, Japan, during 1978
and the XXIV International Congress of Ophthalmology in San Francisco, United States,
during 1982. At the Closing Ceremony of the
latter, Jules François stated that ’’friendship has
gained as much as science and we have felt
close to one another, both in heart and in mind.’’
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*
presented at “Ophthalmologia Belgica”, Brussels,
24th November 2001.
** From the Jules Stein Eye Institute and Department
of Ophthalmology, UCLA School of Medicine,
University of California, Los Angeles, California,
USA
Bull. Soc. belge Ophtalmol., 283, 5-12, 2002.
At the conclusion of his term, grateful colleagues elected Jules François Honorary Life
President of the International Council of Ophthalmology.3
In 1975, Jules François initiated formation of
the Academia Ophthalmologica Internationalis to encourage interaction among academic
ophthalmologists. In recognition, he was accorded the title of Honorary Life President of
the Academia Ophthalmologica Internationalis.
Illustrating the global vision of Jules François,
in April 2001, the International Council of Ophthalmology and the Academia Ophthalmologica Internationalis, working together, published
the International Ophthalmology Strategic Plan
to Preserve and Restore Vision - Vision for the
Future.4 Presented simultaneously in print and
full-text on the Internet (www.icoph.org and
www.acad-ophthal-int.org), this is a multiyear
blueprint for improving eye care throughout the
world.
5
The international leadership of Jules François
and his participation in countless ophthalmology meetings in all parts of the world forged
friendships that united the profession of ophthalmology. With respect and warm memories
of association, it is a distinct honor and a great
personal pleasure to present the Jules François
Memorial Lecture.
In this presentation, I will focus on the role of
randomized clinical trials in determination of
evidence-based medical intervention, results of
the Collaborative Ocular Melanoma Study, and
forward-looking goals of choroidal melanoma
research. The first major publication from a
large, multicenter randomized clinical trial in
ophthalmology was published in the American
Journal of Ophthalmology in 1976, exactly 25
years ago. This report by the Diabetic Retinopathy Study Group changed the global standard of care of proliferative diabetic retinopathy.5 Since then, randomized clinical trials have
influenced the management of nearly every major
pathologic condition in ophthalmology, including corneal disease, cataract, glaucoma,
endophthalmitis, complications of acquired immunodeficiency syndrome (AIDS), retinopathy
of prematurity, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma.6
In the quest for evidence-based medical intervention, a clinical trial may be appropriate when
(1) the disease to be studied is a substantial
public health concern, (2) there is preliminary
evidence that a ’’new’’ test treatment may be
superior to the current ’’standard’’ treatment,
(3) a valid trial outcome may be obtained in a
reasonable time, and (4) ethical patient protection is in place. When these conditions are
met, it is more ethical to conduct a clinical trial than to pursue either the ’’new’’ test treatment or the ’’standard’’ treatment on the basis
of the incomplete or inconclusive evidence. Properly designed, a randomized clinical trial can
control for bias or unascertained factors by randomization, reduce the variability in patient outcome by a suitable sample size, and protect the
participating patients by appropriate ethical safeguards.6
Results of clinical trials are central to evidencebased medical intervention. However, results
are often published over several years in numerous articles that appear in multiple jour6
nals. Computerized search engines such as Medline may not assemble information from an ongoing or completed clinical trial. Recognizing
this, the American Journal of Ophthalmology inaugurated the Clinical Trials Digest as an Internet feature available to all viewers at www.ajo.com in October 2001.7 This Digest is designed to include ongoing and completed trials
that evaluate the effect of treatment (drug, procedure, device, or regimen) in ophthalmic patients. For each listed trial, the Digest presents
the trial design, names of participating centers, and a list of all publications from the trial
by title, date, and authorship. An electronic link
permits the viewer to click on the title of any
publication and immediately review the abstract of the article. This electronic information resource will enable ophthalmologists to locate evidence-based information, alert physicians to new treatment opportunities for their
patients, and foster collaborations within the
global research community.
Illustrating a randomized clinical trial, the Collaborative Ocular Melanoma Study (COMS), in
progress since 1985, is sponsored by the National Eye Institute and National Cancer Institute. The COMS is Chaired by Stuart L. Fine,
M.D.; John D. Earle, M.D. (radiation oncologist), and Bradley R. Straatsma, M.D., are CoChairs; Barbara S. Hawkins, Ph.D., directs the
Coordinating Center; and Natalie Kurinij, Ph.D.,
represents the National Eye Institute. This study
is being conducted at 43 clinical centers in the
United States and Canada.
During 2001, the COMS Randomized Trial of
Iodine 125 Brachytherapy for Choroidal Melanoma presented results in three publications:
characteristics of patients enrolled and not enrolled8, initial mortality findings9, and visual
acuity three years after brachytherapy10. To assess the extent to which findings of the trial can
be generalized to future patients, one report
considered the characteristics of patients enrolled and not enrolled. At the 43 COMS Clinical Centers, 8,712 choroidal melanoma patients were screened between February 1987
and completion of accrual in July 1998, 5,046
had melanoma of eligible size, 2,882 fulfilled
all eligibility criteria, and 1,317 enrolled in the
trial.8 Enrolled patients had choroidal melanoma from 2.5 mm to 10.0 mm in apical height,
no more than 16 mm in longest basal diame-
Fig 1. Standardized gold plaque with insert for I-125 seeds and eyelets for fixation sutures.
ter, and with exceptions, a proximal border 2
mm or more from the optic disk. Eligible patients were adults, free of clinically detectable
melanoma metastasis and with no history of
other primary cancer.
Approximately half (1,371 (46%) of 2,882) of
the eligible patients enrolled. Baseline demographic characteristics and tumor characteristics of enrolled and not-enrolled patients were
well-balanced for all factors judged to be important in determining outcome. Thus, results
of enrolled patients may be generalized to include eligible but not-enrolled patients.
A further question is whether the enrolled patients are broadly representative of patients who
would be candidates for treatment with I-125
brachytherapy. Based on a choroidal melanoma incidence of six to eight new cases per million population per year and a 280 million population in the United States and Canada, there
were about 19,320 to 25,760 new cases of
choroidal melanoma during the 11.5 years of
COMS patient accrual. The 8,718 patients
screened at COMS Centers were 34% to 45%
of all new cases during that time. Moreover,
COMS patients were compared with patients in
other published studies of I-125 brachytherapy. There is considerable variability among stud-
Fig 2. 62-year-old man. Medium choroidal melanoma, right
eye, with basal diameters of 9 mm and 10 mm and apical
thickness of 3.8 mm prior to brachytherapy. Visual acuity:
20/25.
ies, but COMS patients were consistently within the parameters of patients in other studies.
The COMS has high internal validity by design
and by comparison of enrolled and not-enrolled
patients. The COMS has high external validity
based on the proportion of melanoma cases
screened at COMS Centers and comparison of
COMS patients with published reports. We may
conclude that results of the COMS randomized
trial are generalizable to future patients who
meet COMS eligibility criteria.
7
Fig 3. Intraoperative ultrasonography confirms that the I-125 plaque extends 3 mm beyond the border of the melanoma
at 90° intervals around the circumference. Cursers identify tumor border and plaque edge. 85-year-old man with collarbutton shape melanoma measuring 10 mm x 10 mm x 6.3 mm.
In the randomized trial of I-125 brachytherapy, 1,317 patients were enrolled; 660 were assigned randomly to enucleation, and 657 to
I-125 brachytherapy.9 When histopathology
was reviewed centrally, 658 (99.7%) of 660
eyes had choroidal melanoma and 2 eyes had
carcinoma metastatic to the choroid The I-125
brachytherapy protocol provided a dose of 85
Gy at the tumor apex or 5 mm from the interior
surface of the sclera for tumors with apical height
of less than 5 mm. The protocol utilized standard gold plaques that provided a 2 to 3 mm
margin of treatment beyond the tumor border
(Figure 1).
The I-125 plaque placement procedure may be
illustrated by a typical case (Figure 2). Briefly,
under monitored local anesthesia with intravenous sedation or general anesthesia, a conjunctival peritomy was performed and sutures were
looped around the rectus muscle insertions. The
melanoma was localized by transillumination
and ophthalmoscopy, and the sclera was marked
to position the central meridian of the melanoma and identify the placement of each fixation
suture. With the plaque in place and slip knots
on the fixation sutures, plaque placement was
confirmed by intraoperative ultrasonography to
8
assure a 3 mm margin of treatment beyond the
tumor at 90° intervals around the circumference of the melanoma (Figure 3). After confirmation of plaque placement, fixation sutures
were tied and conjunctiva was repositioned to
the limbus.
Based on time of enrollment, 1,072 (81%) of
the patients have been followed after treatment
for 5 years and 416 (32%) for 10 years; 364
patients have died. The unadjusted estimated
5-year survival rates were 81% for enucleation
and 82% for brachytherapy; there was no statistical difference in survival rates (P =.48).
Among COMS patients, survival rates following enucleation and brachytherapy did not differ for up to 12 years after treatment.
In subanalyses and assessment by pathologists,
younger age and shorter longest basal diameter of the tumor were significantly associated
with longer survival. Five year rate of death with
histologically confirmed melanoma metastasis
was approximately 10%, with no statistically
significant difference between enucleation and
brachytherapy.
Important visual acuity data were reported for
623 eyes treated with I-125 brachytherapy and
followed for at least one year.10 At baseline be-
Fig 4. Prior to I-125 brachytherapy. 77-year-old woman
with medium choroidal melanoma, right eye, measuring
8 mm × 11 mm × 4 mm. Proximal edge of the tumor is
4 mm from the foveola. Visual acuity: 20/20.
fore treatment, median protocol visual acuity
in the eye with melanoma was 20/32; 70% of
eyes had 20/40 or better, and 10% of eyes had
20/200 or worse. Three years after I-125
brachytherapy, median visual acuity was 20/
125; 34% of eyes had 20/40 or better and
45% of eyes had 20/200 or worse; the latter
included eyes that were enucleated. Life-table
estimates of patients who lost six or more lines
of visual acuity (a quadrupling of the minimum
angle of resolution) from baseline were 18% by
1 year, 34% by 2 years, and 49% by 3 years
after treatment. Overall, about half of treated
eyes had substantial impairment of visual acuity 3 years after I-125 brachytherapy, defined
as loss of six or more lines of acuity (49% of
eyes) or 20/200 or worse (45% of eyes).
Impairment of visual acuity after brachytherapy is illustrated in an eye with juxtafoveal melanoma and baseline visual acuity of 20/20 (Figure 4). One year after brachytherapy, the tumor is decreased in thickness and visual acuity is 20/25 (Figure 5). Seven years after brachytherapy, the tumor shows further decrease in
thickness, but the peritumor radiation-associated retinopathy and choroidopathy are greater and visual acuity is Count Fingers at 1 foot
(Figure 6).
Radiation retinopathy and radiation optic neuropathy are well-recognized consequences of
radiation therapy. Radiation choroidopathy is
less fully appreciated. Following I-125 brachytherapy, there is a progressive decrease in vascular perfusion of the choroidal melanoma. In
addition, during the 2 years after brachythe-
Fig 5. One year after I-125 brachytherapy. Same patient
as in Figure 4. Decrease in apical thickness of melanoma.
Visual acuity: 20/25.
Fig 6. Seven years after I-125 brachytheray. Same patient
as in Figure 4. Further decrease in melanoma thickness,
extensive peritumor radiation-associated retinopathy and
choroidopathy. No evidence of melanoma metastasis. Visual acuity: Count Fingers at one foot.
rapy, there is a general choroidal vasculopathy
consisting of choriocapillaris nonperfusion, attenuation and closure of small choroidal vessels, and fluorescein staining of residual choroidal vessels. Late choroidal vasculopathy, usually more than 2 years after brachytherapy, includes closure of large choroidal vessels, extensive retinal pigment epithelial atrophy, paving stone degeneration, and remodeling of the
choroidal circulation.11
In broader context, survival results of the I-125
brachytherapy trial should be compared with
the COMS trial of pre-enucleation radiation of
large choroidal melanoma.12, 13, 14 In the preenucleation trial for large melanoma, tumors
were greater than 10 mm in apical height or
greater than 16 mm in longest basal diameter;
9
there was no statistically significant difference
between enucleation with or without pre-enucleation radiation, and 5-year survival was 57
- 62%. In contrast, the brachytherapy trial of
medium choroidal melanoma included tumors
2.5 mm to 10 mm in apical height and less
than 16 mm in longest basal diameter; there
was no difference between enucleation or brachytherapy, and 5-year survival was 81 - 82%.
These results emphasize two forward-looking
melanoma research goals. First, how does radiation therapy affect melanoma cells? Some
affect may be from the attenuation and closure
of blood vessels. However, recent research by
Brantley, Worley, and Harbour15, reported in an
article currently in press in the American Journal of Ophthalmology and described with the
authors’ permission, suggests that radiation induces ’’reproductive cell death.’’ Although the
molecular mechanisms of reproductive cell death
are incompletely understood, most evidence indicates that it results from irreparable damage
to the DNA of the cell. In 3 eyes enucleated for
neovascular glaucoma or periocular pain 2 to
26 months after I-125 brachytherapy and satisfactory tumor response, melanoma cells could
be established in culture. Nonetheless, the irradiated melanoma cells had flattened cell bodies, minimal capacity to divide, and increased
cell death compared to non-irradiated melanoma cells that were plump, divided rapidly, and
formed colonies. For example, in one irradiated eye, estimated tumor doubling time in culture was 375 days with few cells surviving three
passages, while non-irradiated melanoma cells
had a doubling time of 11 days in culture and
continued to grow indefinitely. We must continue to study the molecular mechanisms of radiation and the process of reproductive cell death
to develop new therapies that are increasingly
effective and associated with fewer adverse side
effects.
Second, how can we improve survival of patients with choroidal melanoma? Certainly, patients with medium choroidal melanoma have
a better prognosis than patients with large melanoma. However, some medium melanoma patients who screen negative for melanoma metastasis at the time of brachytherapy or enucleation develop metastatic melanoma. This
probably relates to early onset of melanoma
metastasis. In a study of 70 patients by Eske10
lin and co-authors16, tumor doubling time of
uveal melanoma metastases ranged from 34 to
220 days, with two-thirds between 30 and 80
days, and a median of 63 days. Assuming a
constant growth rate, some melanoma metastasis, had initiated as much as 5 years prior to
primary melanoma treatment. This strengthens the argument for early treatment, but also
indicates the best hope for improving survival
is to combine primary treatment of the choroidal melanoma with adjuvant systemic therapy
to combat micrometastases. Currently in progress
are studies of melanoma antigen by Ericsson
and co-authors18, investigations of ’’tumor killer cells’’ and randomized clinical trials of Allovectin-7 (a gene therapy product which contains the gene for HLA-B7) immunotherapy for
metastatic disease. To date, however, no adjuvant immunotherapy or chemotherapy has been
documented as effective.
In summary, a quarter century after the first
publication from the Diabetic Retinopathy Study,
randomized clinical trials have influenced nearly every major pathologic condition in ophthalmology. In 2001, the Collaborative Ocular Melanoma Study trial of I-125 brachytherapy has
demonstrated that there is no statistically significant difference in survival after enucleation
or I-125 brachytherapy. Three years after brachytherapy, approximately half of treated eyes had
substantial impairment of visual acuity. Fiveyear survival after the I-125 brachytherapy trial for medium melanoma was 81 - 82% but
after the pre-enucleation trial for large melanoma, 5-year survival was 57 - 62%. To improve local tumor control, the molecular mechanisms of radiation-induced reproductive cell
death warrant study. To improve survival, the
best hope is to combine primary treatment of
choroidal melanoma with adjuvant systemic
therapy for micrometastasis.
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